DOI QR코드

DOI QR Code

Protein Tyrosine Phosphatase, Receptor Type B (PTPRB) Inhibits Brown Adipocyte Differentiation through Regulation of VEGFR2 Phosphorylation

  • Kim, Ji Soo (Metabolic Regulation Research Center, Division of BioMedical Sciences, KRIBB) ;
  • Kim, Won Kon (Metabolic Regulation Research Center, Division of BioMedical Sciences, KRIBB) ;
  • Oh, Kyoung-Jin (Metabolic Regulation Research Center, Division of BioMedical Sciences, KRIBB) ;
  • Lee, Eun-Woo (Metabolic Regulation Research Center, Division of BioMedical Sciences, KRIBB) ;
  • Han, Baek Soo (Metabolic Regulation Research Center, Division of BioMedical Sciences, KRIBB) ;
  • Lee, Sang Chul (Metabolic Regulation Research Center, Division of BioMedical Sciences, KRIBB) ;
  • Bae, Kwang-Hee (Metabolic Regulation Research Center, Division of BioMedical Sciences, KRIBB)
  • Received : 2018.10.18
  • Accepted : 2019.02.11
  • Published : 2019.04.28

Abstract

Brown adipocytes have an important role in the regulation of energy balance through uncoupling protein-1 (UCP-1)-mediated nonshivering thermogenesis. Although brown adipocytes have been highlighted as a new therapeutic target for the treatment of metabolic diseases, such as obesity and type II diabetes in adult humans, the molecular mechanism underlying brown adipogenesis is not fully understood. We recently found that protein tyrosine phosphatase receptor type B (PTPRB) expression dramatically decreased during brown adipogenic differentiation. In this study, we investigated the functional roles of PTPRB and its regulatory mechanism during brown adipocyte differentiation. Ectopic expression of PTPRB led to a reduced brown adipocyte differentiation by suppressing the tyrosine phosphorylation of VEGFR2, whereas a catalytic inactive PTPRB mutant showed no effects on differentiation and phosphorylation. Consistently, the expression of brown adipocyte-related genes, such as UCP-1, $PGC-1{\alpha}$, PRDM16, $PPAR-{\gamma}$, and CIDEA, were significantly inhibited by PTPRB overexpression. Overall, these results suggest that PTPRB functions as a negative regulator of brown adipocyte differentiation through its phosphatase activity-dependent mechanism and may be used as a target protein for the regulation of obesity and type II diabetes.

Keywords

References

  1. Bae K-H, Kim WK, Lee SC. 2012. Involvement of protein tyrosine phosphatases in adipogenesis: new anti-obesityk targets. BMB Rep. 45: 700-706. https://doi.org/10.5483/BMBRep.2012.45.12.235
  2. Park A, Kim WK, Bae K-H. 2014. Distinction of white, beige and brown adipocytes derived from mesenchymal stem cells. World J. Stem Cells 6: 33-42. https://doi.org/10.4252/wjsc.v6.i1.33
  3. Cypess AM, Lehman S, Williams G, Tal I, Rodman D, Goldfine AB, et al. 2009. Identification and importance of brown adipose tissue in adult humans. N. Engl. J. Med. 360: 1509-1517. https://doi.org/10.1056/NEJMoa0810780
  4. Harms M, Seale P. 2013. Brown and beige fat: development, function and therapeutic potential. Nat. Med. 19: 1252-1263. https://doi.org/10.1038/nm.3361
  5. Townsend KL, Tseng YH. 2012. Brown adipose tissue: recent insights into development, metabolic function, and therapeutic potential. Adipocyte 1: 13-24. https://doi.org/10.4161/adip.18951
  6. Virtanen KA, Lidell ME, Orava J, Heglind M, Westergren R, Niemi T, et al. 2009. Functional brown adipose tissue in healthy adults. N. Engl. J. Med. 360: 1518-1525. https://doi.org/10.1056/NEJMoa0808949
  7. Hunter T. 1987. A thousand and one protein kinases. Cell 50: 823-829. https://doi.org/10.1016/0092-8674(87)90509-5
  8. Mustelin GS, Feng N, Bottini A, Alonso A, Kholod N, Birle D, et al. 2002. Protein tyrosine phosphatases. Front Biosci. 7: 85-142. https://doi.org/10.2741/A910
  9. Ostman A, Hellberg C, Bohmer FD. 2006. Protein tyrosine phosphatases and cancer. Nat. Rev. Cancer 6: 307-320. https://doi.org/10.1038/nrc1837
  10. Choi HR, Kim WK, Kim EY, Jung H, Kim JH, Han BS, et al. 2012. Protein tyrosine phosphatase profiling analysis of HIB-1B cells during brown adipogenesis. J. Microbiol. Biotechnol. 22: 1029-1033. https://doi.org/10.4014/jmb.1112.12059
  11. Choi HR, Kim WK, Kim EY, Han BS, Min JK, Chi SW, et al. 2013. Dual specificity phosphatase 10 controls brown adipocyte differentiation by modulating the phosphorylation of p38 mitogen-activated protein kinase. PLoS One 8: e72340. https://doi.org/10.1371/journal.pone.0072340
  12. Kim WK, Jung H, Kim D-H, Kim EY, Chung JW, Cho YS, et al. 2009. Regulation of adipogenic differentiation by LAR tyrosine phosphatase in human mesenchymal stem cells and 3T3-L1 preadipocytes. J. Cell Sci. 122: 4160-4167. https://doi.org/10.1242/jcs.053009
  13. Kim WK, Bae K-H, Choi HR, Kim D-H, Choi KS, Cho YS, et al. 2010. Leukocyte common antigen-related (LAR) tyrosine phosphatase positively regulates osteoblast differentiation by modulating extracellular signal-regulated kinase (ERK) activation. Mol. Cells 30: 335-340. https://doi.org/10.1007/s10059-010-0123-y
  14. Kim WK, Jung H, Kim EY, Kim D-H, Cho YS, Park BC, et al. 2011. RPTP${\mu}$ tyrosine phosphatase promotes adipogenic differentiation via modulation of p120 catenin phosphorylation. Mol. Biol. Cell 22: 4883-4891. https://doi.org/10.1091/mbc.e11-03-0175
  15. Kim WK, Oh K-J, Choi HR, Park A, Han BS, Chi SW, et al. 2015. MAP kinase phosphatase 3 inhibits brown adipocyte differentiation via regulation of Erk phosphorylation, Mol. Cell. Endocrinol. 416: 70-76. https://doi.org/10.1016/j.mce.2015.08.023
  16. Choi HR, Kim WK, Park A, Jung H, Han BS, Lee SC, et al. 2013 Protein tyrosine phosphatase profiling studies during brown adipogenic differentiation of mouse primary brown preadipocytes. BMB Rep. 46: 539-543. https://doi.org/10.5483/BMBRep.2013.46.11.058
  17. Bäumer S, Keller L, Holtmann A, Funke R, August B, Gamp A, et al. 2006. Vascular endothelial cell-specific phosphotyrosine phosphatase (VE-PTP) activity is required for blood vessel development. Blood 107: 4754-4762. https://doi.org/10.1182/blood-2006-01-0141
  18. Winderlich M, Keller L, Cagna G, Broermann A, Kamenyeva O, Kiefer F, et al. 2009. VE-PTP controls blood vessel development by balancing Tie-2 activity. J. Cell Biol. 185: 657-671. https://doi.org/10.1083/jcb.200811159
  19. Hayashi M, Majumdar A, Li X, Adler J, Sun Z, Vertuani S, et al. 2013. VE-PTP regulates VEGFR2 activity in stalk cells to establish endothelial cell polarity and lumen formation. Nat. Commun. 4: 1672. https://doi.org/10.1038/ncomms2683
  20. Bagchi M, Kim LA, Boucher J, Walshe TE, Kahn CR, D'Amore PA. 2013. Vascular endothelial growth factor is important for brown adipose tissue development and maintenance. FASEB J. 27: 3257-3271. https://doi.org/10.1096/fj.12-221812
  21. Son MJ, Kim WK, Kwak M, Oh K-J, Chang WS, Min J-K, et al. 2015. Silica nanoparticles inhibit brown adipocyte differentiation via regulation of p38 phosphorylation. Nanotechnology 26: 435101. https://doi.org/10.1088/0957-4484/26/43/435101
  22. Son MJ, Kim WK, Park A, Oh K-J, Kim JH, Han BS, et al. 2016. Set7/9, a methyltransferase, regulates the thermogenic program during brown adipocyte differentiation through the modulation of p53 acetylation. Mol. Cell. Endocrinol. 431: 46-53. https://doi.org/10.1016/j.mce.2016.04.022
  23. Byun SK, An TH, Son MJ, Lee D, Kang HS, Lee EW, et al. 2017. HDAC11 inhibits myoblast differentiation through repression of MyoD-dependent transcription. Mol. Cells 40: 667-676. https://doi.org/10.14348/molcells.2017.0116
  24. Lee D, Choi H, Han BS, Kim WK, Lee SC, Oh K-J, et al. 2016. c-Jun regulates adipocyte differentiation via the KLF15-mediated mode. Biochem. Biophys. Res. Commun. 469: 552-558. https://doi.org/10.1016/j.bbrc.2015.12.035
  25. Lee EW, Oh W, Song HP, Kim WK. 2017. Phosphorylation of p53 at threonine 155 is required for Jab1-mediated nuclear export of p53. BMB Rep. 50: 373-378. https://doi.org/10.5483/BMBRep.2017.50.7.077
  26. Son MJ, Kim WK, Oh K-J, Park A, Lee D, Han BS, et al. 2016. Methyltransferase and demethylase profiling studies during brown adipocyte differentiation. BMB Rep. 49: 388-393. https://doi.org/10.5483/BMBRep.2016.49.7.062
  27. Xue R, Lynes MD, Dreyfuss JM, Shamsi F, Schulz TJ, Zhang H, et al. 2015. Clonal analyses and gene profiling identify genetic biomarkers of the thermogenic potential of human brown and white preadipocytes. Nat. Med. 21: 760-768. https://doi.org/10.1038/nm.3881
  28. Nawroth R, Poell G, Ranft A. 2002. VE-PTP and VE-cadherin ectodomains interact to facilitate regulation of phosphorylation and cell contacts. EMBO J. 21: 4885-4895. https://doi.org/10.1093/emboj/cdf497

Cited by

  1. Crucial lncRNAs associated with adipocyte differentiation from human adipose-derived stem cells based on co-expression and ceRNA network analyses vol.7, 2019, https://doi.org/10.7717/peerj.7544
  2. Roles of Protein Histidine Phosphatase 1 (PHPT1) in Brown Adipocyte Differentiation vol.30, pp.2, 2019, https://doi.org/10.4014/jmb.1909.09003
  3. Protein tyrosine phosphatase, receptor type B is a potential biomarker and facilitates cervical cancer metastasis via epithelial-mesenchymal transition vol.12, pp.1, 2021, https://doi.org/10.1080/21655979.2021.1968250
  4. Vascular Endothelial Protein Tyrosine Phosphatase Regulates Endothelial Function vol.36, pp.2, 2019, https://doi.org/10.1152/physiol.00026.2020